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PubMed1999

Inhaled prostacyclin in the treatment of pulmonary hypertension.

UNLABELLED: Pulmonary hypertension can occur primarily with an unknown aetiology or secondary in association with cardiac or pulmonary disorders such as congenital diaphragmatic hernia, idiopathic respiratory distress syndrome, acute respiratory distress syndrome (ARDS), congenital heart disease with malformation of the pulmonary blood vessels, chronic obstructive lung disease and following cardiac surgery. Prostacyclin (PGI(2)), an arachidonic acid metabolite, has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in assessing the reversibility of the disorder prior to surgical interventions. While the intravenous application of PGI(2) can cause a decrease not only of the pulmonary but also of the systemic vascular tone, aerosolised PGI(2) results in a selective pulmonary vasodilation without affecting the systemic blood pressure. Furthermore, aerosolised PGI(2) can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilation/perfusion ratio such as ARDS, due to the redistribution of pulmonary blood flow from nonventilated to ventilated, aerosol-accessible lung regions. CONCLUSION: Aerosolised prostacyclin can be a valuable tool in the treatment and diagnostic evaluation of elevated pulmonary vascular resistance and impaired pulmonary gas exchange. Reservations must be made for its long-term use, as its short half-life necessitates continuous inhalation.

Administration, Inhalation↗
PubMed1990

[Persistent pulmonary hypertension of newborn. The PFC syndrome].

Persistent pulmonary hypertension of the newborn (PPHN), initially described by Gersony et al as persistent foetal circulation (PFC syndrome), results from a flawed transition from foetal to extrauterine pulmonary circulation. It is characterised by the maintenance of a high pulmonary vascular resistance and right-to-left shunting through the ductus arteriosus and foramen ovale. Infants with a wide variety of underlying clinical conditions develop PPHN. According to Rudolph three main anatomic types of PPHN can be identified: normal pulmonary vascular development increased pulmonary vascular smooth muscle development decreased cross-sectional area of pulmonary vascular bed. It is important to realize that several pathophysiologic mechanisms may coexist and interact. Besides metabolic and respiratory acidosis, hypercapnia and hypoxaemia some other factors induce pulmonary vasoconstriction. Thromboxane, leukotrienes and prostaglandins play a decisive role. Since PPHN can be associated with a broad spectrum of clinical conditions, a specific clinical picture is lacking. The baby is usually term or post-term, cyanotic immediately after birth or some hours later. Birth asphyxia, hyperviscosity, sepsis and aspiration of meconium have been recognized as predisposing factors. The diagnosis can be confirmed by echocardiography. Contrast echo will indicate right-to-left shunting with normal anatomy. Currently hyperventilation, tolazolin, chlorpromazin and dopamine/dobutamine have been advocated as central foci for clinical therapy. Recently prostacyclin was introduced as a specific pulmonary vasodilatator.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiography↗
PubMed1981

Utility of M-mode echocardiography for early identification of infants with persistent pulmonary hypertension of the newborn.

The clinical syndrome of persistent pulmonary hypertension of the newborn (PPHN) still carries high mortality in spite of improved neonatal care. The purpose of this prospective study was to assess the utility of M-mode echocardiography for the early identification of infants with PPHN prior to clinical deterioration. Echocardiograms of 51 infants who needed fractional inspiratory oxygen (FIO2) greater than or equal to 0.25 to maintain adequate PaO2 within 36 hours of life were compared to those of 115 healthy full-term and preterm newborns. Of the 51 infants, ten had elevated systolic time interval ratios of both ventricles simultaneously (ventricular pre-ejection period to ventricular ejection time [RPEP/RVET greater than or equal to 0.50, LPEP/LVET greater than 0.38]). All of these newborns had PPHN that was manifest clinically by 11 to 30 hours of age. The echocardiographic findings preceded clinical deterioration by at least one to five hours in all cases. The other 41 infants had clinical courses consistent with uncomplicated pulmonary disease. These data indicate that systolic time interval ratios, although not accurate measures of pulmonary arterial pressure and/or pulmonary vascular resistance, permit early identification of infants with PPHN and separation from others with uncomplicated pulmonary disease.

Echocardiography↗
PubMed2003

Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review.

Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with multiple causes, with an incidence of 0.43-6.8/1,000 live births and a mortality of 10-20%. Survivors have high morbidity in the forms of neurodevelopmental and audiological impairment, cognitive delays, hearing loss, and a high rate of rehospitalization. The optimal approach to the management of PPHN remains controversial. Inhaled nitric oxide (iNO) is currently regarded as the gold standard therapy, but with as many as 30% of cases failing to respond, has not proven to be the single magic bullet. Given the complex pathophysiology of the disease, any such magic bullet is unlikely. A number of recent studies have suggested a role for specific phosphodiesterase (PDE) inhibitors in the management of PPHN. Sildenafil, a specific PDE5 inhibitor, appears the most promising of such agents. We aim to review the current status and limitations of iNO and the potential of PDE inhibitors in the management of PPHN. The reasons why caution is warranted before specific PDE5 inhibitors like sildenafil are labelled as potential magic bullets for PPHN will be discussed. The need for randomized-controlled trials to determine the safety, efficacy, and long-term outcome following treatment with sildenafil in PPHN is emphasized.

Dipyridamole↗
PubMed1997

Extracorporeal circulation increases nitric oxide-induced methemoglobinemia in vivo and in vitro.

OBJECTIVES: Methemoglobinemia is a well-known side effect of nitric oxide inhalation. We tested the hypothesis whether cardiopulmonary bypass increases methemoglobin formation by nitric oxide. DESIGN: A two-phase study: a) a controlled, prospective in vivo study of inhaled nitric oxide treatment followed by b) a second, prospective and controlled in vitro study. SETTING: Pediatric intensive care unit and research laboratory in a university hospital. PATIENTS: The in vivo study consisted of 25 patients following open-heart surgery and 19 children with acute respiratory distress syndrome (ARDS) or persistent pulmonary hypertension of the newborn. The in vitro study consisted of 20 patients with and 20 patients without cardiopulmonary bypass. INTERVENTIONS: For the in vivo study, methemoglobin measurements were taken before and after application of 20 parts per million (ppm) of nitric oxide. For the in vitro study, red blood cells of patients were incubated with 32 ppm nitric oxide before and after surgery. Methemoglobin, glutathione, adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NADH/NADHP) concentrations were compared. MEASUREMENTS AND MAIN RESULTS: For the in vivo study, nitric oxide inhalation increased methemoglobin from 0.2 +/- 0.1% to 1.2 +/- 0.7% in patients receiving nitric oxide after open-heart surgery and from 0.2 +/- 0.1% to 0.5 +/- 0.4% in ARDS/persistent pulmonary hypertension of the newborn patients (p < .01). For the in vitro study, nitric oxide incubation of red blood cells increased methemoglobin concentration from 3.7 +/- 1.9% preoperatively to 7.4 +/- 2.4% after open-heart surgery. This increase was not observed in patients who did not undergo cardiopulmonary bypass (3.6 +/- 1.6% vs. 3.6 +/- 1.9%; p < .001). In erythrocytes of patients undergoing extracorporeal circulation, there was no difference between pre- and postoperative glutathione, ATP, and NADH/NADPH concentrations. CONCLUSIONS: Cardiopulmonary bypass is an important risk factor for methemoglobinemia when inhaled nitric oxide is applied. This risk is not secondary to diminished concentrations of energetic substrates.

Administration, Inhalation↗
PubMed1992

Persistent pulmonary hypertension in premature neonates with severe respiratory distress syndrome.

Cardiac catheterization studies have demonstrated that Doppler-derived flow velocities in the ductal flow jet and the left pulmonary artery accurately predict the aortopulmonary pressure difference and left-to-right shunt size in newborns. To assess the presence of persistent pulmonary hypertension in premature newborns with various degrees of respiratory distress syndrome (RDS) severity, we estimated pulmonary artery pressure from the aortopulmonary pressure difference and pulmonary blood flow from the left pulmonary artery flow velocity with color-flow-directed, pulsed Doppler echocardiography. Seventy-nine premature neonates were divided into three groups--no or mild RDS (n = 27), severe RDS (n = 38), and fatal RDS (n = 14)--and compared with a group of healthy term neonates (n = 34). In premature and term neonates with no/mild RDS the mean +/- SEM aortopulmonary pressure difference increased from 7.3 +/- 0.4 and 6.6 +/- 0.5 mm Hg to 22.8 +/- 1.4 and 21.4 +/- 1.1 mm Hg over the first 24 hours (P < .001). The mean aortopulmonary pressure difference was 0.9 +/- 0.3 mm Hg during the first 72 hours in neonates with fatal RDS, but increased from 1.5 +/- 0.3 mm Hg at 4 hours to 7.4 +/- 0.6 at 24 hours and 21.5 +/- 0.7 mm Hg at 72 hours of age in neonates with severe RDS. Left pulmonary artery velocity time integrals were 18.3 +/- 0.5 cm in premature and 18.8 +/- 0.5 cm in term neonates with no/mild RDS at 12 hours vs 11.2 +/- 0.4 cm in neonates with severe and 9.9 +/- 0.5 cm in neonates with fatal RDS (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗
PubMed2002

Inhaled nitric oxide and gentle ventilation in the treatment of pulmonary hypertension of the newborn--a single-center, 5-year experience.

OBJECTIVE: To evaluate the effect of inhaled nitric oxide (INO) in pulmonary hypertension of the newborn (PH) in a single center over 5 years using gentle ventilation (GV), without hyperventilation or induced alkalosis. METHODS: Data from 229 consecutive infants with PH of varied etiology treated with INO and GV, and from 67 infants with meconium aspiration syndrome (MAS) and primary PH (PPHN) treated with GV alone were reviewed over a 5-year period (86% outborn). INO was initiated at 25 ppm when PH and severe hypoxemia persisted despite maximal optimal ventilation. Hyperventilation or systemic alkalosis were not attempted. RESULTS: Mean duration of ventilation was 9.9 +/- 14 days (median 6.5 days). Average mean airway pressure (MAP) dropped from 17.7 +/- 4.3 cm H(2)O at the referral hospital to 13.2 +/- 2.5 cm H(2)O (p < 0.001) following admission to our unit using conventional settings and GV, before starting INO. Mean oxygenation index (OI) dropped from 46.8 +/- 24.5 to 22.7 +/- 21.4 within 24 hours of INO therapy (p < 0.001). Infants with higher baseline pH and lower baseline OI responded better to INO (p < 0.02). Overall survival was 72%. Patients with MAS and PPHN had the best response, 92% survived and there was a 46% reduction in need for extracorporeal membrane oxygenation (ECMO) compared to historical pre-INO period controls (23.9% vs. 12.8%, p < 0.01). In the infants treated with GV alone, the MAP dropped from 17.2 +/- 4.3 cm H2O at the referral hospital to 12.6+/-2.4 after GV was started in our unit. CONCLUSIONS: We conclude that INO is an effective and well-tolerated therapy for PH in infants receiving GV.

Academic Medical Centers↗
PubMed1998

[The prevalence and characteristics of persistent pulmonary hypertension of the newborn. A multicenter study. The Study Group of the Società Italiana di Cardiologia Pediatrica (SICP)].

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is a rare syndrome with a severe prognosis, in which a prompt diagnosis can be life-saving. The aim of our study was to verify its prevalence in a neonatal population, define clinical and echocardiographic criteria for the diagnosis of PPHN and discuss therapeutic choices. METHODS: The following clinical and echocardiographic criteria for the diagnosis of PPHN were defined: 1. cyanosis and hypoxemia non-responsive to O2 therapy; 2. right to left shunt at an atrial or ductal level. All neonates fulfilling these criteria referred to the neonatal units of seven pediatric or general hospitals over a two-year period were enrolled. RESULTS: From January 1995 to December 1996, thirty neonates with PPHN (8%) were observed. Birth was pre-term in 5 out of 30. Ten (33%) had experienced chronic and/or fetal asphyxia (FA). Death occurred in 7 (22%), four of whom with FA. Echocardiography showed tricuspid insufficiency in 18 (60%); mean pulmonary systolic pressure was 67 +/- 16 mmHg (range 41-95). In 23 surviving neonates, normalization of clinical and echocardiographic parameters occurred in 8 +/- 5 days. THERAPY: In most neonates, vasodilators (tolazoline, prostacyclin) and/or nitric oxide were employed. CONCLUSIONS: PPHN is confirmed to be a rare pathological condition; prognosis is severe, particularly in neonates with FA. Echocardiography is a reliable non-invasive method for a prompt diagnosis and follow-up. Subsequent studies are needed to assess therapeutic choices.

Echocardiography↗
PubMed1993

Fetal ductus arteriosus ligation. Pulmonary vascular smooth muscle biochemical and mechanical changes.

To evaluate the smooth muscle mechanical and biochemical changes associated with persistent pulmonary hypertension syndrome of the newborn, we studied 31 fetal sheep in which the ductus arteriosus was ligated at 125 days of gestation. Sixty-one noninstrumented and six sham-operated fetuses served as controls. All animals were delivered by cesarean section at 137-140 days of gestation, and the experimental group had the ductus arteriosus ligated for 12 +/- 3 days. The ligated group demonstrated a higher mean (+/- SEM) pulmonary artery pressure (72.3 +/- 3.8 versus 54.1 +/- 2 mm Hg, p < 0.01) and right ventricular mean free wall weight (12.5 +/- 0.7 versus 6.8 +/- 0.3 g, p < 0.01) as compared with the sham-operated group. Significant changes in the pulmonary vascular smooth muscle of the ligated group were observed. The myosin content of vessels from the second through fifth generation demonstrated a significant increase in actin and myosin content (p < 0.01), but given their disproportional changes, the noninstrumented group demonstrated a lower actin/myosin ratio than the experimental group (p < 0.01). Changes in the myosin heavy chain isoform stoichiometry, characterized by an increase in both the mean high/low myosin heavy chain isoform ratio (1.8 +/- 0.3 versus 1.0 +/- 0.1, p < 0.05) and the nonmuscle isoform as a percentage of the total myosin heavy chain (12.4 +/- 0.7% versus 2.7 +/- 0.9%, p < 0.01), were also observed in the ligated as compared with the noninstrumented animals. In addition, the muscle Mg-ATPase activity was significantly (p < 0.05) reduced in the experimental group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Orthotopic transplantation for total anomalous pulmonary venous connection associated with complex congenital heart disease.

BACKGROUND: When total anomalous pulmonary venous connection is associated with other complex cardiac malformations, early and late postsurgical morbidity and mortality are excessive. METHODS: In an attempt to modify this outcome, twelve children (4 days to 6.8 years of age) with total anomalous pulmonary venous connection and various congenital cardiac defects were treated with orthotopic heart transplantation. Associated cardiac diagnoses included the following: hypoplastic left heart syndrome (n = 2), unbalanced atrioventricular canal with pulmonary atresia (n = 2), and single ventricle with severe pulmonary stenosis (n = 3) or atresia (n = 5). Two patients had situs inversus, and two had dextrocardia with situs ambiguous. Eight patients had asplenia and one had polysplenia. Palliative pretransplantation procedures in five patients included the following: systemic to pulmonary artery shunt (n = 5), atrioventricular valve annuloplasty (n = 1) and classical Glenn shunt (n = 1). The donor left atrium was anastomosed directly to a common pulmonary venous pool in nine patients; whereas three children required complex reconstruction to baffle the pulmonary venous flow to the donor left atrium. RESULTS: There was one operative death related to an oversized heart and vena caval thrombosis. Follow-up ranged from 16 months to 4.5 years (average 3 years). In two patients (18%) pulmonary venous obstruction developed 3 and 4 months after transplantation. Reoperation to relieve the obstruction was successful in one patient. The second patient underwent three such reoperations and died of sepsis 10 months after orthotopic heart transplantation. CONCLUSION: Orthotopic transplantation is a viable option for children with complex total anomalous pulmonary venous connection that precludes a biventricular repair. Transplantation may improve the dismal prognosis of those children, but it does not eliminate the potential for late pulmonary venous obstruction.

Child↗
PubMed2001

Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn.

Respiratory distress syndrome (RDS) and development of bronchopulmonary dysplasia (BPD) are characterized by endothelial cell damage. Persistent pulmonary hypertension of the newborn (PPHN) is a disorder that alters the pulmonary microvasculature. Immunohistochemistry for VEGFA(165), an endothelial cell mitogen, and its receptor Flt-1, was performed on lung tissues from autopsies from four fetuses, three preterm infants, four term infants without primary lung disease, four infants with BPD, and four infants with PPHN. VEGF was measured in tracheal aspirates from 31 preterm infants, 5 intubated term infants without primary lung injury, and 12 infants with PPHN during the first 10 postnatal days, and from 8 infants with BPD. Immunohistochemistry for VEGF and Flt-1 was similar in fetuses, preterm infants, and term infants: for VEGF mostly in bronchial epithelium and alveolar macrophages, and for Flt-1 mostly in vascular endothelial cells and bronchial epithelial cells. In patients with BPD, and PPHN, staining for VEGF and Flt-1 appeared also in Type II pneumocytes. Preterm infants with more severe RDS had lower VEGF than those who recovered. The persistent expression of VEGF and Flt-1 during the fetal and neonatal period supports a physiological role for VEGF in human lung development. The lower pulmonary VEGF in preterm infants with more severe RDS may contribute to the pathophysiology of the acute lung injury. In BPD, the expression of VEGF in alveolar epithelium may represent a compensatory increase after the acute phase of the lung disease. In PPHN, that more cell types express VEGF and Flt-1, and the tendency toward a higher concentration of pulmonary VEGF may represent enhanced production of VEGF in response to impaired endothelial function.

Acute Disease↗
PubMed1996

Low-dose inhaled nitric oxide for neonates with pulmonary hypertension.

OBJECTIVE: Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilation-perfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN. METHODOLOGY: Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm. RESULTS: After 30 min exposure to iNO, the arterial oxygen tension (PaO2) rose from a median of 49 mmHg (6.5 kPa) [range 12-82 mmHg (1.6-10.9 kPa)] to 75 mmHg (10 kPa) [range 17-450 mmHg (2.3-60 kPa)] (P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iNO 20) (P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iNO 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9 +/- 2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss. CONCLUSIONS: Inhaled NO reduces the oxygenation index by improving the PaO2 and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.

Child Development↗
PubMed2001

Analysis of nonsteroidal antiinflammatory drugs in meconium and its relation to persistent pulmonary hypertension of the newborn.

OBJECTIVE: The objective of this study was to detect fetal exposure to nonsteroidal antiinflammatory drugs (NSAIDs) by meconium analysis and to determine the relationship between fetal exposure to NSAIDs and the development of persistent pulmonary hypertension of the newborn (PPHN). METHODS: In a case-control study of the inborn and outborn nurseries of a large urban medical center, meconium was collected from 101 newborn infants (40 with the diagnosis of PPHN based on clinical or echocardiographic criteria and 61 randomly selected, healthy, term infants [control]) and analyzed for NSAIDs (ibuprofen, naproxen, indomethacin, and aspirin) by gas chromatography/mass spectrometry. The risk of developing PPHN was determined in infants who were exposed antenatally to NSAID. RESULTS: Infants with PPHN (n = 40) had a mean gestation of 38.9 weeks and birth weight of 3524 g, which were similar to the those of the control group (n = 61). However, the incidence of low Apgar scores (</=6) at 1 minute and 5 minutes was significantly higher in the PPHN group than in the control group. The diagnoses associated with PPHN were primary PPHN (25%), meconium aspiration syndrome (35%), respiratory distress syndrome (20%), low Apgar score/asphyxia (12.5%), and pneumonia/sepsis (8%). Mean duration of ventilator support for the PPHN group was 11 days. Nitric oxide (NO) was given to 19 infants (47.5%) for a mean duration of 25.4 hours. Fourteen of the 19 infants who were treated with NO (74%) required extracorporeal membrane oxygenation, and 2 died. The overall incidence of positive NSAID in meconium in the study population (n = 101) was 49.5%: 22.8% were positive for ibuprofen, 18.8% for naproxen, 7.9% for indomethacin, and 43.6% for aspirin. There was poor agreement (Cohen's kappa = 0.09) between maternal history of NSAID use and NSAID detection in meconium. PPHN was significantly associated with 1) the presence of at least 1 NSAID in meconium (odds ratio [OR] = 21.47; 95% confidence interval [CI] = 7.12-64.71) or 2) the presence in meconium of aspirin (OR = 8.09; 95% CI = 3.27-20.10), ibuprofen (OR = 12.89; 95% CI 3.93-42.32), or naproxen (OR = 3.31; 95% CI = 1.17-9.33). By logistic regression analysis, low Apgar scores at 1 and 5 minutes and the antenatal exposure to aspirin, naproxen, and ibuprofen were significantly associated with PPHN and treatment with inhaled NO or extracorporeal membrane oxygenation. CONCLUSION: We confirm by meconium analysis the results of previous studies that demonstrated that the use of NSAIDs during pregnancy, particularly aspirin, ibuprofen, and naproxen, is high; is grossly underestimated by maternal history; and is significantly associated with PPHN. Thus, the easy access to over-the-counter NSAIDs of pregnant women should be reevaluated, and the potential dangers of these drugs to the newborn infant should be more effectively promoted.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Comparison of the pulmonary vasculature in newborns and stillborns with congenital diaphragmatic hernia.

The purpose of this study was to compare structural changes in the pulmonary vasculature in newborns with congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) and stillborns with CDH. Victorian blue van Gieson (VVG) staining and immunostaining with anti-alpha smooth-muscle actin (ASMA) was performed on lung tissue obtained at autopsy from 23 newborns with CDH complicated by PPH, 7 stillborns with CDH, and 11 age-matched controls with sudden infant death syndrome (SIDS). The degrees of adventitial and medial thickness and area were measured in pulmonary arteries with an external diameter (ED) of <75 micrometers, 75-100 micrometers, 100-150 micrometers, 150-250 micrometers, 250-500 micrometers, and >500 micrometers by image analyzer and compared statistically. The degrees of adventitial and medial thickness and area were measured in pulmonary veins with an ED of <100 micrometers, 100-200 micrometers, and >200 micrometers by image analyzer and compared statistically. In order to determine whether the characteristic structural changes were size-related, each was related to ED. There was a significant increase in adventitial thickness and area in arteries of all sizes in both newborns and stillborns with CDH compared to SIDS patients (P < 0. 05). The degree of medial thickness in newborns and stillborns with CDH was significantly increased compared to SIDS patients (P < 0.01). The degree of medial area was significantly increased for arteries with ED less than 100 micrometers (P < 0.05) in newborns and stillborns with CDH compared with SIDS patients. There was a significant increase in adventitial thickness and area in veins of all sizes in newborns with CDH compared to stillborns with CDH and SIDS (P < 0. 05). The degree of adventitial thickness and area of pulmonary veins were similar in stillborns with CDH and SIDS. There were no significant differences in medial thickness of veins between the three groups. The presence of abnormally thick-walled pulmonary arteries in stillborns with CDH suggests that the intrapulmonary arteries in CDH may become excessively muscularized during fetal life, becoming unable to adapt normally at birth. The absence of structural changes in pulmonary veins in stillborns with CDH suggests that the pulmonary venous changes observed in newborns with CDH complicated by PPH occur after birth as a result of increases in transvascular pressure or a response to release of peptide growth factors.

Case-Control Studies↗
PubMed1998

Adventitial changes in pulmonary vasculature in congenital diaphragmatic hernia complicated by pulmonary hypertension.

PURPOSE: The purpose of this study was to characterize structural changes in the pulmonary vasculature in congenital diaphragmatic hernia (CDH) complicated by persistent pulmonary hypertension (PPH) with particular emphasis on adventitial thickness. METHODS: Victorian blue Van Gieson (VVG) staining and immunostaining with antialpha smooth muscle actin (ASMA) were performed on lung tissues obtained at autopsy from 23 patients with CDH complicated by PPH and 11 age-matched control tissues of sudden infant death syndrome patients (SIDS). The degree of medial and adventitial thickening was measured in pulmonary arteries with an external diameter (ED) of less than 75 microm, 75 to 100 microm, 100 to 150 microm, 150 to 250 microm, 250 to 500 microm, and greater than 500 microm by IPS-4.01 image analyzer and compared statistically. The degree of medial thickening and adventitial thickening was also measured in pulmonary veins with an ED of less than 100 microm, 100 to 200 microm, and greater than 200 microm. To determine whether the characteristic structural changes were size related, each was related to ED. The area of adventitia and media of the pulmonary arteries and veins was measured using image analyzer. RESULTS: There was a significant increase in medial and adventitial thickness in arteries of all sizes in CDH patients compared with controls (P < .01). The degree of adventitial area was significantly increased for arteries of all sizes (P < .01) and the degree of medial area was significantly increased only for arteries less than 100 microm size (P < .05) in CDH patients compared with controls. Calculation of the areas of the various components in the wall of each artery showed that for small arteries (<100 microm ED), the area of the lumen was smaller, and the areas of the media and adventitia were larger in CDH patients compared with controls (P < .01). There was a significant increase in adventitial thickness and area in veins of all sizes in CDH patients compared with controls (P < .01). The adventitial thickness of pulmonary veins were ED of less than 100 microm: CDH, 13.5 microm +/- 3.5; control, 9.21 microm +/- 2.0; ED 100 to 200 microm: CDH, 21.3 microm +/- 7.5; control, 13.0 microm +/- 4.8; ED greater than 200 microm: CDH, 34.4 microm +/- 12.5; control, 22.3 microm +/- 4.2. CONCLUSIONS: The present study provides the first quantitative demonstration of structural alterations in pulmonary veins in addition to pulmonary arteries in CDH complicated by PPH. The structural remodeling of the pulmonary vein is perhaps as a result of an increase in transvascular pressure in PPH.

Actins↗
PubMed1997

Improved oxygenation in a randomized trial of inhaled nitric oxide for persistent pulmonary hypertension of the newborn.

OBJECTIVE: To determine the effect of inhaled nitric oxide (NO) on clinical outcome in newborns with persistent pulmonary hypertension (PPHN). DESIGN: A prospective, randomized trial of patients referred to a level 3 nursery in a single large center. Clinicians were not masked to group assignment. Crossover of patients from control to NO treatment was not permitted. METHODS: We randomized 49 mechanically ventilated newborns, transferred to our center with clinical and echocardiographic evidence of severe PPHN (arterial oxygen tension [PaO2] <100; fractional inspired oxygen = 1) to treatment with or without NO. Patients with gestational age <34 weeks or with congenital heart disease or diaphragmatic hernia were excluded. High-frequency oscillatory ventilation was used but not allowed concomitantly with NO. Primary outcome variables were oxygenation, mortality, and use of extracorporeal membrane oxygenation (ECMO). RESULTS: Meconium aspiration syndrome and isolated PPHN were the most common diagnoses (32/49) and were distributed equally between groups. The median age at the time of entry into the study was similar between groups, 25 hours for control patients and 18 hours for NO patients. Median baseline oxygenation index (OI) was similar in 23 control (OI = 29) and 26 NO (OI = 30) patients. Mortality (8%), use of ECMO (33%), median days on mechanical ventilation (9 days), and duration of supplemental oxygen (13 days) were not different between treatment groups. PaO2, oxygen saturation, and OI improved in the NO group compared with baseline and to control patients at 15 minutes. The median percent change in OI (-31%) in the NO group was significantly different from baseline and from the control group. The difference in oxygenation between treatment groups was still apparent 12 hours after baseline. Before cannulation for ECMO, oxygenation was better in the NO group compared with control patients. Among patients who were placed on ECMO, the median time from baseline to ECMO cannulation was 2.4 hours (range, 1 to 12 hours) among control patients and 3.3 hours (range, 2 to 68 hours) for those randomized to receive NO. There was a tendency to observe fewer adverse neurologic events (seizure and intracranial hemorrhage) in the NO group (4/26 vs 8/23). One child with alveolar capillary dysplasia confirmed by postmortem examination could not be weaned from 80 parts per million of NO and transiently developed methemoglobinemia (peak methemoglobin level = 17%). No other side effects were observed. CONCLUSIONS: Although mortality and ECMO use were similar for both treatment groups using this study size and design, sustained improvement in oxygenation with NO and better oxygenation at initiation of ECMO may have important clinical benefits. We speculate that modification of treatment to include specific lung expansion strategies with NO treatment and recognition that early improvement of oxygenation may be sustained with NO may lead to reduced use of ECMO in NO treated patients compared with controls.

Administration, Inhalation↗
PubMed2000

Delayed-onset sensorineural hearing loss in a 3-year-old survivor of persistent pulmonary hypertension of the newborn.

Persistent pulmonary hypertension of the newborn (PPHN) and its conventional medical treatment are associated with sensorineural hearing loss, yet current recommendations for regular audiological evaluations of PPHN survivors are lacking. We report a case of delayed-onset, progressive sensorineural hearing loss in a 3-year-old patient with a history of PPHN and a normal auditory brainstem evoked response at 6 weeks of age. The relatively late detection of significant sensorineural hearing loss in this otherwise healthy 3-year-old illustrates the need for audiological evaluation at regular intervals in patients with a history of PPHN.

Child, Preschool↗